HIV-1-specific CD8+ T cells play an important role in controlling HIV-1 virus replication during acute infection. In contrast, the antiviral efficacy of HIV-1-specific CD8+ T cell responses during chronic infection is less apparent, and an increasing body of evidence indicates a functional impairment of these responses in chronic infection. However, very little is known about the precise factors leading to the impairment of antiviral activity of HIV-1-specific CD8+ T cell responses in chronic infection in humans. Data from persistent viral infections in the mouse model have demonstrated that both the deletion of virus-specific T cell clones as well as the functional impairment of persistent T cell responses, in particular in the absence of T help, contribute to the reduction of virus-specific immunity. Preliminary data presented in this proposal indicate that similar mechanisms can be observed in HIV-1 infected humans, and may lead to the alteration of HIV-1-specific CD8+ T cell function. To precisely determine the factors that lead to the impairment of an initially effective antiviral immune response, the PI proposes to study the evolution of HIV-1-specific CD8+ T cell function starting in acute HIV-1 infection in a unique cohort of subjects identified within the first weeks of HIV-1 infection, that has been characterized in detail for the specificity of their HIV-1-specific T cell responses during the initial funding cycle of this grant. Studies proposed in the first specific aim will characterize the clonotypic composition and function of the first wave of HIV-1-specific CD8+ T cell responses that are dominant in acute infection and their evolution over time. The second specific aim will investigate the impact of subsequent destruction of HIV-1-specific T cell help on HIV-1-specific CD8+ T cell function by comparing the function of "helped" and "helpless" CD8+ T cell populations. The third specific aim will build on these studies and test the potential of reconstituting HIV-1-specific CD8+ T cell function in chronic infection by selective reconstitution of T help using immunotherapeutic interventions. Taken together, the proposed studies, representing a direct extension of the work performed during the initial funding cycle, will provide crucial insights into our understanding of antiviral CD8+ T cell immunity in acute HIV-1 infection, the factors leading to the impairment of virus-specific CD8+ T cell function and the potentials for the reconstitution of CD8+ T cell function using immunotherapeutic interventions.